EP1326621A2

EP1326621A2 - Medicinal composition and in particular its use in fluid therapy

Info

Publication number: EP1326621A2
Application number: EP01975890A
Authority: EP
Inventors: Pascal Gustin; Carole Cambier; Thierry Unté Catholique de Louvain CLERBAUX; Albert Unté Catholique de Louvain FRANS; Bruno Detry
Original assignee: Universite Catholique de Louvain UCL; Universite de Liege ULG
Current assignee: Universite Catholique de Louvain UCL; Universite de Liege ULG
Priority date: 2000-10-16
Filing date: 2001-10-16
Publication date: 2003-07-16
Anticipated expiration: 2021-10-16
Also published as: WO2002032393A3; WO2002032393A2; ES2238484T3; DE60109184T2; AU9530101A; DE60109184D1; ATE289820T1; EP1326621B1; CA2425699A1; US20040033268A1

Abstract

The invention concerns a medicinal composition comprising, in therapeutically efficient amounts, hypertonic sodium chloride, at least a molecule directly or indirectly providing a relaxing effect on the vascular smooth muscles, and at least a molecule capable of supplying an exogenous phosphate input.

Description

DRUG COMPOSITION AND IN PARTICULAR ITS USE IN FLUIDOTHERAPY

The present invention relates to a new medicinal composition, and in particular to its use in fluid therapy.

In cattle, toxo-infectious pathologies, including neonatal diarrhea and endotoxin shock, require such treatment.

With regard to neonatal diarrhea, it is commonly accepted that the first treatment to be initiated is oral or parenteral fluid therapy, depending on the clinical condition of the animal. However, current therapies are only aimed at restoring water and ion balance, restoring blood pH and covering a possible energy deficit. Until now, the treatment usually recommended in the scientific literature dealing with parenteral fluid therapy in cattle is based on the administration of large volumes of isotonic crystalloid solutions, the amounts infused being calculated based in particular on the degree of dehydration and acidosis of the animal. In order to restore the circulating volume, other authors also recommend the administration of small volumes of a hypertonic saline solution, with or without dextran added. According to the literature, these saline solutions must be accompanied by the administration of an alkalizing agent in order to restore the blood pH. It therefore appears that to date, the tissue oxygenation disorders existing in diarrheal calves are never taken into account in the evaluation of the efficacy of the treatment. More serious, in some cases, current therapies can even worsen these tissue oxygenation disorders. Indeed, by for example, the massive administration of bicarbonates in order to restore the pH can cause relative alkalosis and hypochioremia, thus favoring the increase in the affinity of hemoglobin for oxygen and rendering the transport of oxygen by the less efficient blood.

With regard to endotoxin shock, it is also recognized that the initiation of treatment with parenteral fluid therapy is a priority. However, it essentially aims to restore the circulating volume. The scientific literature describes the use of different infusion solutions, namely: isotonic crystalloid solutions, hypertonic crystalloid solutions (with or without a colloid such as dextran), but also plasma and whole blood. The effects of these different therapies on hemoglobin oxygen transport and tissue oxygenation have not, however, been studied in depth.

Furthermore, US patents 5,238,684, 5,236,712, 5,147,650, 5,089,477 and 4,981,687 describe formulations intended to be administered preferably by oral route, which aim to increase the physiological response to exercise, especially via an increase in cardiac output. These solutions contain water, electrolytes, glycerol and an additional source of energy. These solutions are not intended to manipulate the transport of oxygen by hemoglobin, nor to improve tissue oxygenation.

The present invention aims to develop a new drug composition. This must be able to fight against tissue hypoxia which occurs during toxic-infectious pathologies, in mammals, in particular in ruminants, such as cattle, and including human beings. During these pathological processes, the invention must make it possible to maintain in oxygen-affected beings their oxygen consumption thanks, in particular, to an increase in the amount of oxygen extracted from the tissues, while combining this original mechanism with an increase in cardiac output.

To solve this problem, there is provided, according to the invention, a medicinal composition comprising, in therapeutically effective amounts, hypertonic sodium chloride, at least one molecule directly or indirectly exerting a relaxation effect on the vascular smooth muscles, and at least one molecule capable of providing an exogenous supply of phosphates. This composition includes a therapeutic "tripod" necessary to guarantee the targeted therapeutic success. It acts by a combination of original action mechanisms allowing a better extraction of oxygen at the tissue level, namely a decrease in the intrinsic affinity of hemoglobin for oxygen, an increase in vivo of the transport of oxygen through hemoglobin and an increase in the intrinsic ability of tissues to extract oxygen. The best extraction of oxygen at the tissue level prevents the development of tissue hypoxia.

According to one embodiment of the invention, the composition further comprises an basifying agent capable of increasing a blood pH in a range compatible with adequate oxygen transport. This alkalizing agent in adequate quantity allows maintenance of the relative acidosis. As basifying agents, there may be mentioned, inter alia, bicarbonates, acetates, propionates and lactates, in particular sodium bicarbonate.

According to an advantageous form of the invention, the composition consists of a combination of a first infusion solution and a second infusion solution, the first infusion solution comprising water, said hypertonic sodium chloride and said au minus one molecule exerting a relaxation effect, and the second infusion solution comprising water, and said at least one molecule capable of providing an exogenous supply of phosphates. Thanks to this embodiment, administered by infusion, for example intravenously, it is possible to increase the cardiac output which reinforces the phenomenon of oxygen extraction at the tissue level.

Such a formulation allows separate production and storage of the components as well as possibly a chronologically separate administration of the two solutions, depending on the speed of action of the components envisaged. It also allows, if necessary, a simultaneous infusion of the two solutions in two different places of the body to be treated and a spread application over time of these solutions.

According to the invention, sodium chloride is at a concentration of 5 to 10% in said first infusion solution. Advantageously, use will be made of doses of approximately 5 to 10 ml / kg of body weight. By molecule exerting a smooth muscle relaxation effect can be understood, according to the invention, vasodilators in general, and caffeine in particular. The term “molecule capable of providing an exogenous supply of phosphates” can be understood according to the invention to mean an inorganic phosphate, for example sodium phosphate, or an organic phosphate, such as a triphosphate, for example adenosine triphosphate, or diphosphoglycerate, as well as in general any substance capable of modifying the intra-erythrocytic content of diphosphoglycerate.

According to a particular form of the invention, the second infusion solution also contains at least one component intended to correct the water, electrolyte and energy balance. By component of this kind, one can understand sodium chloride, potassium chloride, glucose, etc. Other medicinal compositions according to the invention are indicated in the claims given below, as well as the use of these compositions for the manufacture of a medicament intended for the therapeutic or prophylactic treatment of hypoxic tissue disorders, in particular those occurring during toxi-infectious pathologies, in mammals.

The invention will now be described in detail with the aid of examples given below without implied limitation.

Example 1

Under normal conditions, the transport of dissolved oxygen represents only a small proportion (about 1%) of the total transport. For the rest, the oxygen is conveyed to the tissues after fixation on the hemoglobin. In the lungs, hemoglobin becomes saturated with oxygen.

In resting tissues, about a third of the total amount thus fixed diffuses into the interstitial fluid, the rest returning to the lungs. The fixation of oxygen on hemoglobin depends above all on the partial pressure of oxygen (PO ₂ ) in the plasma. Conventionally, in all mammals, the regulating factors of the oxygen affinity for hemoglobin are the blood pH, the body temperature, the partial pressure of carbon dioxide, the fixing rate of 2,3-diphosphoglycerate ( 2.3 DPG) on hemoglobin. These mechanisms allow the exchange of oxygen in the body. In arterial blood, the partial pressure of oxygen is high, the temperature and the CO ₂ contents decrease, while the pH increases, as many conditions favorable to the fixing of oxygen on hemoglobin. In venous blood and in tissues, on the contrary, the partial pressure of oxygen is low, the pH decreases, the temperature and the CO ₂ contents increase, all factors favorable to the release of oxygen.

During a study aimed at investigating tissue oxygenation disorders in diarrheal calves, by considering the organism no longer as a whole, but in a vital body territory in particular, it was able to be demonstrated that an adaptation of this oxygenation by an increase in the extraction of oxygen at the tissue level did not exist in all the organs. The ability of tissues to extract oxygen even appeared to be reduced. It appeared that, if we consider the exchanges occurring between arterial blood and venous jugular blood, diarrheal calves suffer from an inability to extract the oxygen supplied to them by the blood. This incapacity can be explained by: - an increase in the affinity of oxygen for hemoglobin, illustrated by the reduction in the partial pressure of oxygen to 50% saturation of hemoglobin measured under standard conditions (pH: 7.4; PCO ₂ : 40 mm Hg; temperature: 37 ° C), hereinafter called standard P50 (P50 std). This phenomenon is explained in particular by a decrease in the rate of 2.3 DPG; - hypothermia and hypocapnia, which oppose the positive effects of acidosis on oxygen transport by the blood, as illustrated by the drop in partial oxygen pressures to 50% hemoglobin saturation in the arterial (P50a) and venous (P50v) compartments; - an intrinsic inability of the tissues to extract the oxygen which is supplied to them, as illustrated by the increase in the partial pressure of oxygen at the venous level (PvO ₂ ) in diarrheal calves.

In the present example, therefore, a series of treatments for diarrheal calves has been carried out by a conventional method, by a commercial product, by different components. of a composition according to the invention and by a composition according to the invention, for purposes of comparison.

In all the examples below, the dosages are calculated with respect to 1 kg of body weight. a) The conventional solution tested is an isotonic crystalloid solution of sodium chloride (40 ml / kg), glucose (20 ml / kg) and sodium bicarbonate, to be infused. The amount of sodium bicarbonate to bring is calculated as follows: number of mmoles of bicarbonate to bring = Weight (kg) x base deficiency in venous blood (mmoles / l) x 0.6 (l / kg), where 0 , 6 represents the volume of distribution of bicarbonate in the extracellular fluid compartment. Infusion rate:

50 ml / kg / h the first hour, then 20 ml / kg / h. b) The commercial solution, Lactetrol ^R , is a drug indicated for the correction of dehydration, accompanied or not by metabolic acidosis, in cattle. It is important to note that this product is one of the rare drugs available on the market for the treatment, by parenteral fluid therapy, of symptoms associated with neonatal diarrhea. The specialty's formula is as follows:

Sodium chloride 5.76 mg

Potassium chloride 0.37 mg

Calcium chloride 0.37 mg

Magnesium chloride 0.2 mg Sodium lactate 5.04 mg

Methyl parahydroxybenzoate Water for injection ad 1 ml.

Volume to be administered: 40 ml / kg. Infusion rate: 10 ml / kg / h. c) A composition made up of two infusion solutions: - hypertonic solution A (7.5% NaCl, 5 ml / kg, 1 ml / kg / min): this solution being at the limit of the osmolarity allowed in therapy, the elements aiming to restore the ionic balance and maintain the water balance and the pH are brought via a solution B, administered separately.

- isotonic solution B (glucose: 20 ml / kg and sodium bicarbonate administered in sufficient quantity to reduce the base deficit to zero). This solution can possibly be supplemented by other ions (K ⁺ , g ⁺⁺ ...). Administration speed: 50 ml / kg / h the first hour, then 20 ml / kg / h.

The amount of sodium bicarbonate to be supplied is calculated as previously described. d) A composition consisting of two infusion solutions: hypertonic solution A (NaCl 7.5%, 7.5 ml / kg supplemented with 0.4 g of caffeine per liter; 1 ml / kg / min): this solution being the osmolarity limit allowed in therapy, the elements aimed at restoring the ionic balance and maintaining the water balance and the pH are brought separately via solution B. solution B (isotonic NaCl + glucose: 10 g / l + potassium chloride: 1 g / l: 40 ml / kg and isotonic sodium bicarbonate administered in sufficient quantity to bring the pH to 7.2). This solution can possibly be supplemented by other ions (Mg ⁺⁺ ...). Administration speed: 20 ml / kg / h. The amount of sodium bicarbonate to bring was calculated according to the Henderson-Hasselbalch equation. e) A composition constituted as follows: isotonic sodium chloride + glucose: 10 g / l + potassium chloride: 1 g / l: 40 ml / kg, and isotonic inorganic phosphates (NaH ₂ P0 ₄ .H ₂ O: 2, 45 g / l, Na ₂ HPO ₄ .2H ₂ O: 19.82 g / l): 16 ml / kg. This solution can possibly be supplemented by other ions (Mg ⁺⁺ ...). Administration speed: 27.5 ml / kg / h. f) Composition according to the invention consisting of two infusion solutions: solution A:

Apyrogenic sterile water hypertonic NaCI (7.5%): 75 g / l Caffeine: 0.4 g / l

(7.5 ml / kg; infusion rate: 1 ml / kg / min) solution B:

Apyrogenic sterile water.

Isotonic buffer solution of inorganic phosphates (NaH ₂ PO ₄ .H ₂ O: 2.45 g / l, Na ₂ HPO ₄ .2H ₂ 0: 19.82 g / l): 16 ml / kg; infusion rate: 25 ml / kg / h. In order to restore blood volume, correct the electrolyte balance and maintain the pH within limits compatible with the transport of oxygen (7,2), various compounds can be added to this solution, namely: NaCI, KCI , MgCI ₂ , glucose, NaHCO ₃ .

For example: isotonic sodium chloride solution + glucose 10 g / l + potassium chloride 1 g / l (40 ml / kg) and isotonic sodium bicarbonate if necessary (pH <7.2).

Each of these compositions was tested on a sample of approximately 10 diarrheal calves. It should be noted that in the case of compositions formed from two solutions, solution B was infused 15 minutes after the start of the infusion of solution A.

FIG. 1 illustrates the evolution over time of the quantity of oxygen extracted at the tissue level (OER) following the administration of each of the compositions a) to f). OER is the ratio of the difference in oxygen content in arterial (CaO ₂ ) and venous (CvO ₂ ) blood to oxygen content in the arterial blood. In practice, the arterial content and the venous oxygen content are calculated as follows:

CaO ₂ = Hb x BO ₂ x [SaO _2/100] + (α x _PaO2) CvO ₂ = Hb x BO ₂ x [SvO _2/100] + (α x PvO ₂₎

where Hb represents the hemoglobin level of the animal, BO ₂ represents the quantity of oxygen fixed by the hemoglobin (1.39 mlO ₂ / g Hb) and α represents the coefficient of solubility of oxygen (0.003 ml .100ml ^"1. Mm Hg ^{" 1} ).

The fraction of oxygen extracted at the tissue level is then expressed as a ratio: OER = (CaO ₂ - CvO ₂ ) / CaO ₂

From this figure 1 it can be deduced that the conventional treatment a) and the Lactetrol solution b) are not capable of increasing the extraction of oxygen at the tissue level.

While we had noticed a favorable effect of the chlorine ion on oxygen transport in vivo, in healthy calves (Cambier et al, Effects of hyperchloremia on blood oxygen binding in healthy calves, The American Physiological Society, 1998, p. 1267-1272), this treatment (composition c)) unfortunately proved incapable of increasing the extraction of oxygen from the tissue of diarrheal calves, this parameter even tending to decrease. The results obtained in vivo in healthy calves cannot therefore be transposed to sick calves.

Finally, it appears with composition d) a slight increase in the quantity of oxygen extracted, which however is not found to be significant, while composition e) and the composition according to the invention f) exhibit a significant and lasting increase thereof.

However, the advantage of the composition according to the invention f) compared to composition e) appears when the variations of the OER recorded during treatment are compared with the initial values of OER measured at T0 (FIG. 2). A significant negative correlation is observed with the two treatments. This means that the animals with the most marked deficiencies from the point of view of the OER derive the greatest benefit from the therapies. However, comparing the two solutions e) and f), it appears that the increases in OER obtained with composition e) are less than those obtained with the composition according to invention f), as shown by the ordinates at l origin of the equations of the linear regressions relating to these two treatments (respectively 0.17 for the composition e) and 0.38 for the composition according to the invention f).

In addition, it should be emphasized that only the composition according to the invention f) involves all the mechanisms allowing an increase in the extraction of oxygen at the tissue level. This phenomenon can prove to be very important in pathological conditions, one mechanism being able to replace the other in the event of deficiency.

As a reminder, the extraction of oxygen at the tissue level can be improved via three mechanisms: 1. by a decrease in the intrinsic affinity of hemoglobin for oxygen. This phenomenon is illustrated by an increase in the

P50 std. Figure 3 shows a significant increase in

P50 std during the administration of the composition e) and during the administration of the composition according to the invention f) when no significant effect is obtained, or even only effects noxious (decrease in standard P50) are recorded, along with other treatments. 2. by a modification, in vivo, of the factors controlling the transport of oxygen by the blood, and in particular the pH. The beneficial effects recorded, in vitro, on P50 std (see point 1) can thus be increased or decreased in animals. In vivo, the oxygen transport capacity by the blood is evaluated by calculating the partial pressures of oxygen P50 a and P50 v. Ideally, an increase in P50 a and P50 v is desired, by strengthening, notably through variations in pH, the effects on

P50 std.

As illustrated in FIGS. 4 and 5, in vivo, composition e) and the composition according to the invention f) improve the oxygen transport capacities. However, with regard to composition e), this effect is mainly due to the decrease in the intrinsic affinity of hemoglobin for oxygen, illustrated by the increase in P50 std. This phenomenon is only slightly strengthened in vivo. Thus, at t = 2 hours, if the composition e) increases the P50 std by 8%, the P50 a and P50 v are only increased by 10 and 9% respectively, showing the absence of other intervention mechanisms favorable to the release of oxygen at the tissue level. In vivo, the intervention of these regulatory mechanisms of oxygen transport can be very important in animals whose standard P50 increases only slightly following the infusion. Thus the effects obtained on the standard P50 with composition e) are variable. As proof, at t = 2 hours, the increase in standard P50 varies from 4 to 13% depending on the individual, and only 33% of the animals treated with composition e) maintain an increase in standard P50 for 24 hours. In these animals, the use of other regulatory mechanisms would be necessary. Unlike solution e), the composition according to the invention f) allows, in addition to the increase in standard P50, the development of hyperchloremia and the maintenance of relative acidosis, two elements reinforcing the effects on standard P50 and favorable to the release of oxygen at the tissue level. The weight of these various mechanisms varies over time. Thus, at t = 1 hour, the composition according to the invention f) induces an increase in the standard P50 of only 1% but increases the P50 a and P50 v, respectively by 11 and 8%, due to the development of hyperchloremia and maintenance of relative acidosis. At t = 24 hours, the balance between these two functions is reversed, since the role played by changes in the intrinsic affinity of hemoglobin for oxygen becomes preponderant;

3. by an increase in the capacity of tissues to extract oxygen, marked by a decrease in the partial oxygen pressure at the venous level (PvO ₂ ). As illustrated in FIG. 6, the hypertonic composition c) significantly increases the PvO ₂ . The administration of a vasodilator, simultaneously with a hypertonic solution (composition d) or the absence of a hypertonic solution, as is the case with composition e), makes it possible to cancel this effect. By combining a vasodilator, a hypertonic solution of NaCl and the phosphates, according to the composition according to the invention f), the natural capacity of the tissues to extract oxygen is optimal and is maintained throughout the treatment.

The methods for determining PvO ₂ and P50 are described for example in C. Cambier et al., American Journal of Veterinary Research, 61, 2000, p. 299-304. In addition to these three mechanisms involved in increasing oxygen extraction at the tissue level, an infusion solution can also induce beneficial effects via hemodynamic changes (increased cardiac output). According to the data in the literature, and based on our own experience in calves suffering from endotoxin shock (see example 3), hypoxia can result:

- an alteration in the oxygen supply by the blood (DO ₂ ) consecutive, in particular, to hemodynamic disturbances (reduction in cardiac output),

- a decrease in the extraction of oxygen at the tissue level, which has just been discussed.

These two mechanisms combine in varying degrees in individuals suffering from toxi-infectious pathologies to result in the hypoxic states observed clinically. It is therefore essential to have therapeutic solutions that improve all of these functions, using all possible mechanisms. The solution according to the invention, in addition to its effects on the OER, improves the OD ₂ due to the increase in cardiac output linked to fluid intake but above all to a hyperosmotic effect in the intravascular compartment. FIG. 8 illustrates the increase in OD ₂ recorded in calves suffering from endotoxin shock and treated with the composition according to the invention.

The administration of an isotonic solution, like solution e), can induce an increase in cardiac output due to water intake, but this effect remains limited and delayed over time compared to the almost immediate and significant effects of hypertonic solutions. , like the composition according to the invention f).

In summary, in addition to having a more significant original effect on the EDO (see Figure 2) than solution e), the following solution the invention f) therefore acts on all the mechanisms capable of fighting against disorders of oxygen extraction at the tissue level.

In addition, it exerts immediate and significant hemodynamic effects due to its direct but also hyperosmotic effects.

Example 2

A comparative test was carried out on three samples of. diarrheal calves. The first sample (n = 12) was subjected to the conventional treatment a) described in Example 1, the second sample (n = 18) with Lactetrol and the third sample (n = 16) with the composition according to the invention f ) from Example 1.

A clinical score was then established for treated calves by analyzing the symptoms of the disease, and incorporating assessments such as decreased sucking reflex, slower threat reflex, decreased tactile sensitivity, decreased the ability to stand, etc. The score is 0 for healthy calves and 13 for a comatose animal. The results of this evaluation are collated in Table 1 below.

Table 1

N.D.: not determined. Trt: treatment

The values are expressed as follows: means ± SE.

*: value significantly different from the value recorded at TO in the same group ( ^* : p <0.05, * ^* : p <0.01, * ^** : p <0.001) t: value significantly different from the value recorded at the same time in the conventional treatment group (t: p <0.05)

Δ: value significantly different from the value recorded at the same time in the lactetrol ^R treatment group (Δ: p <0.05, ΔΔ: p <0.01).

Example 3

Systemic disorders of oxygen extraction at the tissue level having been demonstrated during endotoxin shock, a comparative test was carried out on two samples of healthy calves having received an intravenous injection of endotoxins of Escherichia coli serotype 055: B5, 0.2 μg / kg, at time -30 minutes. At time 0, a first sample (n = 3) is subjected to the treatment of a composition according to the invention and a second sample (n = 3) is not subjected to any treatment.

As shown in FIG. 7, contrary to what has been observed in untreated animals, the composition according to the invention makes it possible to maintain the oxygen consumption (VO ₂ ) at its basic level, or even to increase it, thus preventing the development of tissue hypoxia. This maintenance, even this increase, is made possible thanks to the following mechanisms: ^" a maintenance of the quantity of oxygen brought to the tissues by the blood (DO ₂ ), due in particular to the increase in cardiac output (hemodynamic effect) . The evolution of OD ₂ is shown in Figure 8; • an increase in the oxygen extraction capacity at the tissue level, illustrated in FIG. 9.

This increase in OER is explained by the same phenomena as those described in diarrheal calves.

Example 4 A comparative trial was carried out according to the methodology described for example 3. During this trial, a clinical score was established according to the criteria described for example 2.

The results of this evaluation are collated in Table 2 below.

Table 2

The values are expressed as follows: means ± SE.

^* : value significantly different from the value recorded at T-30 (physiological value) in the same group (*: p <0.05, **: p <0.01)

Δ: value significantly different from the value recorded T0 in the same group (Δ: p <0.05).

It should be understood that the present invention is in no way limited to the embodiments described above and that many modifications can be made thereto without departing from the scope of the appended claims.

One can for example envisage a composition in the form of at least one solid formulation, for example a powder or a soluble or effervescent tablet, intended for the constitution of minus an aqueous infusion solution by mixing with water. Thus, one can easily store the components of the composition according to the invention and prepare the solutions to be perfused just before administration.

Claims

1. Medicinal composition comprising, in therapeutically effective amounts, hypertonic sodium chloride, at least one molecule which directly or indirectly exerts a relaxation effect on the vascular smooth muscles, and at least one molecule capable of providing an exogenous supply of phosphates.

2. Composition according to claim 1, characterized in that it further comprises an basifying agent capable of increasing a blood pH in a range compatible with adequate oxygen transport.

3. Composition according to either of Claims 1 and 2, characterized in that it is in the form of at least one aqueous solution.

4. Composition according to claim 3, characterized in that it consists of a combination of a first infusion solution and a second infusion solution, the first infusion solution comprising water, said hypertonic sodium chloride and said at least one molecule exerting a relaxation effect, and the second infusion solution comprising water, and said at least one molecule capable of providing an exogenous supply of phosphates.

5. Composition according to either of Claims 1 and 2, characterized in that it is in the form of at least one solid formulation intended for the constitution of at least one aqueous infusion solution by mixing with water.

6. Composition according to claim 4, characterized in that the hypertonic sodium chloride is at a concentration of 5 to 10% in said first infusion solution.

7. Composition according to any one of claims 1 to 6, characterized in that said at least one molecule capable of providing an exogenous supply of phosphates is chosen from the group consisting of inorganic phosphates, organic phosphates or modifiers of the content diphosphoglycerate intra-erythrocytic.

8. Composition according to any one of claims 4 to 7, characterized in that the second perfusion solution also contains an alkalizing agent capable of increasing the blood pH in a range compatible with adequate oxygen transport.

9. Composition according to any one of claims 2 to 8, characterized in that the basifying agent is chosen from the group consisting of bicarbonates, acetates, propionates and lactates.

10. Composition according to any one of claims 4 to 8, characterized in that the second infusion solution also contains at least one component intended to correct the water, electrolyte and energy balance.

11. Composition according to claim 10, characterized in that said at least one component intended to correct the balance is chosen from the group consisting of sodium chloride, potassium chloride and glucose.

12. Composition according to any one of claims 1 to 11, for the implementation of a therapeutic or prophylactic treatment of hypoxic tissue disorders, in particular of those occurring during toxic-infectious pathologies, in mammals.

13. Composition according to claim 12, for use in the treatment of neonatal diarrhea and endotoxin shock in ruminants.

14. Composition according to any one of claims 4 to 11, as a combination product of the first infusion solution and the second infusion solution intended for simultaneous, separate or spread over time thereof in a therapeutic treatment or prophylactic of hypoxic tissue disorders, in particular those occurring during toxi-infectious pathologies, in mammals.

15. Use of a composition according to any one of claims 1 to 11, for the manufacture of a medicament intended for the therapeutic or prophylactic treatment of hypoxic tissue disorders, in particular of those occurring during toxi-infectious pathologies, in mammals.